M. Manning, W. H. Sawyer and coworkers have published a series of publications describing various [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)-4-valine]-arginine-vasopressin congeners which have antivasopressin activity. Representative of these are EPA No. 61,356, U.S. Pat. No. 4,367,225 and U.S. Pat. No. 4,399,125.
All of the Manning compounds have a tripeptide chain attached at unit 6 and are, or course, nonapeptides. The present compounds are distinguished over these by being octapeptides, by having a des-Gly dipeptide tail attached at unit 6 and by having potent vasopressin antagonist activity.
The potent biological activity of the compounds of the present invention is unexpected in view of the fact that des-glycinamide.sup.9 -vasopressin and des-lysine.sup.8 -desglycinamide.sup.9 -vasopressin [T. Barth et al., Collection Czechoslov. Chem. Commun. 39, 506 (1974)] as well as desglycine.sup.9 -oxytocin [B. Berde et al., Handb. Exp. Pharm 23 860 (1968)] retain little of the activity of their respective parent compounds. In fact, Barth reports that desglycinamide.sup.9 -AVP has CNS activity but practically no antidiuretic or uterotonic activity, Belgian Patent No. 896,509.
Certain of the peptide art designations used in the specification and claims are the following: Cap, .beta.-mercapto-.beta.,.beta.-cycloalkylenepropionic acid; Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Chg, cyclohexylglycine; Abu, .alpha.-amino-n-butyric acid; Cha, cyclohexylalanine; Pba, aminophenylbutyric acid, Gln, glutamine; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Phe(4'-Alk), lower alkylphenylalanine; Val, valine; Nva, norvaline; Ile, isoleucine; Nle, norleucine; D-aIle, D-allo-isoleucine; Leu, leucine; Ala, alanine; Lys, lysine; Arg, arginine; Asn, asparagine; Met, methionine; Tos, tosylate; HF, hydrogen fluoride; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; HBT, 1-hydroxybenzotriazole; ADH, antidiuretic hormone; ACM, acetamidomethyl; DMAP, dimethylaminopyridine.
When the term "vasopressin" is used, in the specification only, it means L-arginine vasopressin (AVP) unless otherwise modified. The AVP derivatives of this invention are preferred. "Alk" represents a lower alkyl of 1-4 carbons which is optionally attached to the nitrogen at Y, to the oxygen substituent of the tyrosine unit when such is present at position 2 or to the phenyl ring of a phenylalanine unit at ring position 3. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl.
Therefore, in the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form.